Viral infection dynamics with immune chemokines and CTL mobility modulated by the infected cell density.

We study a viral infection model incorporating both cell-to-cell infection and immune chemokines. Based on experimental results in the literature, we make a standing assumption that the cytotoxic T lymphocytes (CTL) will move toward the location with more infected cells, while the diffusion rate of CTL is a decreasing function of the density of infected cells. We first establish the global existence and ultimate boundedness of the solution via a priori energy estimates. We then define the basic reproduction number of viral infection R 0 and prove (by the uniform persistence theory, Lyapunov function technique and LaSalle invariance principle) that the infection-free steady state E 0 is globally asymptotically stable if R 0 < 1 . When R 0 > 1 , then E 0 becomes unstable, and another basic reproduction number of CTL response R 1 becomes the dynamic threshold in the sense that if R 1 < 1 , then the CTL-inactivated steady state E 1 is globally asymptotically stable; and if R 1 > 1 , then the immune response is uniform persistent and, under an additional technical condition the CTL-activated steady state E 2 is globally asymptotically stable. To establish the global stability results, we need to prove point dissipativity, obtain uniform persistence, construct suitable Lyapunov functions, and apply the LaSalle invariance principle.

Viral dynamics with immune responses: effects of distributed delays and Filippov antiretroviral therapy.

In this paper, we propose a general viral infection model to incorporate two infection modes (virus-to-cell mode and cell-to-cell mode), the CTL immune response, and the distributed intracellular delays during the processes of viral infection, viral production, and CTLs recruitment. We investigate the existence, the uniqueness, and the global stability of three equilibria: infection-free equilibrium [Formula: see text], immune-inactivated equilibrium [Formula: see text] and immune-activated equilibrium [Formula: see text], respectively. We prove that the viral dynamics are determined by two threshold parameters: the basic reproduction number for infection [Formula: see text] and the basic reproduction number for immune response [Formula: see text]. We also numerically explore the viral dynamics beyond stability. We use bifurcation diagrams to show that increasing the delay in CTL immune cell recruitment can induce a switch in viral load from a stable constant level to sustained oscillations, and then back to a stable equilibrium. We also compare the contributions of the two infection modes to the total infection level and identify the key parameters that would affect the percentages of virus-to-cell infection and cell-to-cell infection. Finally, we explore how Filippov control can be applied in antiretroviral therapy to reduce the viral loads.

The importance of quarantine: modelling the COVID-19 testing process.

We incorporate the disease state and testing state into the formulation of a COVID-19 epidemic model. For this model, the basic reproduction number is identified and its dependence on model parameters related to the testing process and isolation efficacy is discussed. The relations between the basic reproduction number, the final epidemic and peak sizes, and the model parameters are further explored numerically. We find that fast test reporting does not always benefit the control of the COVID-19 epidemic if good quarantine while awaiting test results is implemented. Moreover, the final epidemic and peak sizes do not always increase along with the basic reproduction number. Under some circumstances, lowering the basic reproduction number increases the final epidemic and peak sizes. Our findings suggest that properly implementing isolation for individuals who are waiting for their testing results would lower the basic reproduction number as well as the final epidemic and peak sizes.

Circ-FAT1 Up-Regulates FOSL2 Expression by Sponging miR-619-5p to Facilitate Colorectal Cancer Progression.

Circular RNA FAT atypical cadherin 1 (circ-FAT1) has been reported to play roles in colorectal cancer (CRC) development. Here, the purpose of this study was to investigate the function and mechanism of circ-FAT1 in CRC tumorigenesis and its potential value in the clinic. Levels of genes and proteins were examined by quantitative real-time polymerase chain reaction and Western blot. In vitro assays were conducted using cell counting kit-8 assay, 5-Ethynyl-2'-deoxyuridine assay, flow cytometry, transwell assay, and tube formation assay, respectively. The target relationship between miR-619-5p and circ-FAT1 or FOS-like antigen 2 (FOSL2) was verified by dual-luciferase reporter and RNA immunoprecipitation assays. In vivo assay was performed using a mouse subcutaneous xenograft model. Circ-FAT1 and FOSL2 were highly expressed in CRC tissues and cells. Functionally, knockdown of circ-FAT1 or FOSL2 suppressed CRC cell apoptosis, migration, invasion, and angiogenesis, but induced cell apoptosis in vitro. Mechanistically, circ-FAT1 acted as a sponge for miR-619-5p to up-regulate the expression of FOSL2, which was confirmed to be a target of miR-619-5p. A series of rescue experiments demonstrated that miR-619-5p inhibition or FOSL2 overexpression reversed the inhibitory action of circ-FAT1 silencing on CRC cell malignant phenotypes mentioned above. Pre-clinically, lentivirus-mediated circ-FAT1 knockdown inhibited the tumorigenesis of CRC xenografts in nude mice via regulating miR-619-5p and FOSL2. Circ-FAT1 knockdown repressed FOSL2 expression by sponging miR-619-5p to suppress CRC tumorigenesis, providing a potential approach for CRC therapeutics.

A New Class of Weighted CUSUM Statistics.

A change point is a location or time at which observations or data obey two different models: before and after. In real problems, we may know some prior information about the location of the change point, say at the right or left tail of the sequence. How does one incorporate the prior information into the current cumulative sum (CUSUM) statistics? We propose a new class of weighted CUSUM statistics with three different types of quadratic weights accounting for different prior positions of the change points. One interpretation of the weights is the mean duration in a random walk. Under the normal model with known variance, the exact distributions of these statistics are explicitly expressed in terms of eigenvalues. Theoretical results about the explicit difference of the distributions are valuable. The expansions of asymptotic distributions are compared with the expansion of the limit distributions of the Cramér-von Mises statistic and the Anderson and Darling statistic. We provide some extensions from independent normal responses to more interesting models, such as graphical models, the mixture of normals, Poisson, and weakly dependent models. Simulations suggest that the proposed test statistics have better power than the graph-based statistics. We illustrate their application to a detection problem with video data.

Threshold dynamics of a nonlocal and delayed cholera model in a spatially heterogeneous environment.

A nonlocal and delayed cholera model with two transmission mechanisms in a spatially heterogeneous environment is derived. We introduce two basic reproduction numbers, one is for the bacterium in the environment and the other is for the cholera disease in the host population. If the basic reproduction number for the cholera bacterium in the environment is strictly less than one and the basic reproduction number of infection is no more than one, we prove globally asymptotically stability of the infection-free steady state. Otherwise, the infection will persist and there exists at least one endemic steady state. For the special homogeneous case, the endemic steady state is actually unique and globally asymptotically stable. Under some conditions, the basic reproduction number of infection is strictly decreasing with respect to the diffusion coefficients of cholera bacteria and infectious hosts. When these conditions are violated, numerical simulation suggests that spatial diffusion may not only spread the infection from high-risk region to low-risk region, but also increase the infection level in high-risk region.

First known case of successful pressure ulcer treatment in a lung transplant patient with post-COVID-19 pneumonia.

Given the current COVID-19 crisis, multiple clinical manifestations and related complications of COVID-19 disease, especially in lung transplant patients following post-COVID-19 pneumonia, are a major challenge. Herein, we report the therapeutic course of the first reported case of sacrococcyx pressure ulcers (PU) in a 65-year-old male COVID-19 patient who underwent lung transplantation and developed a PU following surgery. We used a combination of regulated negative pressure-assisted wound therapy system (RNPT, six treatment courses, five days per treatment course), a skin tension-relief system (an intraoperative aid in minimising wounds caused by sacrococcygeal PUs) and a gluteus maximus myocutaneous flap to repair sacrococcygeal wounds. This successfully treated case provides a reference point for the treatment of similar cases.

Human umbilical cord mesenchymal stem cell-derived and dermal fibroblast-derived extracellular vesicles protect dermal fibroblasts from ultraviolet radiation-induced photoaging in vitro.

Ultraviolet B (UVB) radiation is a major cause of aging in dermal fibroblasts. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show antioxidant activity. In this study, the anti-aging effects of MSC-EVs on dermal fibroblast photoaging induced by UVB radiation were evaluated, and the effects of extracellular vesicles derived from dermal fibroblasts (Fb-EVs) were compared. Human umbilical cord mesenchymal stem cells and human dermal fibroblasts were cultured, and MSC-EVs and Fb-EVs were isolated and characterized. Human dermal fibroblasts were cultured in the absence or presence of different concentrations of EVs 24 hours prior to UVB radiation exposure. Cell proliferation and cell cycle were evaluated, and senescent cells and intracellular ROS were detected. The expressions of matrix metalloproteinase-1 (MMP-1), extracellular matrix protein collagen type 1 (Col-1), and antioxidant proteins such as glutathione peroxidase 1 (GPX-1), superoxide dismutase (SOD), and catalase were also analyzed. Pretreatment with MSC-EVs or Fb-EVs significantly inhibited the production of ROS induced by UVB radiation, increased dermal fibroblast proliferation, protected cells against UVB-induced cell death and cell cycle arrest, and remarkably decreased the percentage of aged cells. Pretreatment with MSC-EVs or Fb-EVs promoted the expressions of GPX-1 and Col-1 and decreased the expression of MMP-1. Both MSC-EVs and Fb-EVs protected dermal fibroblasts from UVB-induced photoaging, likely through their antioxidant activity.

Resonance of Periodic Combination Antiviral Therapy and Intracellular Delays in Virus Model.

There is a substantial interest in detailed models of viral infection and antiviral drug kinetics in order to optimize the treatment against viruses such as HIV. In this paper, we study within-viral dynamics under general intracellular distributed delays and periodic combination antiviral therapy. The basic reproduction number [Formula: see text] is established as a global threshold determining extinction versus persistence, and spectral methods are utilized for analytical and numerical computations of [Formula: see text]. We derive the critical maturation delay for virus and optimal phase difference between sinusoidally varying drug efficacies under various intracellular delays. Furthermore, numerical simulations are conducted utilizing realistic pharmacokinetics and gamma-distributed viral production delays for HIV. Our results demonstrate that the relative timing of the key viral replication cycle steps and periodic antiviral treatment schedule involving distinct drugs all can interact to critically affect the overall viral dynamics.

Cell-Free Fat Extract Increases Dermal Thickness by Enhancing Angiogenesis and Extracellular Matrix Production in Nude Mice.

BACKGROUND: Although adipose-derived stem cells (ADSCs) and nanofat exert antiaging effects on skin, they contain cellular components that have certain limitations in clinical practice. Cell-free fat extract (Ceffe) is a fraction purified from nanofat through removal of cellular components and lipid remnants that contains various growth factors. OBJECTIVES: The purpose of this study was to evaluate the effects of Ceffe on cultured human dermal fibroblasts in vitro and on the dermis of nude mice in vivo. METHODS: In the in vitro study, human dermal fibroblasts were cultured with Ceffe for 72 hours, followed by flow cytometry measurement of cell proliferation and cell cycle. In the in vivo study, different concentrations of Ceffe were injected into the dorsal skin of nude mice for 4 weeks. The thickness of the dermis; proliferation of cells; density of the capillary; and expressions of type I and III collagen (Col-1 and Col-3), matrix metalloproteinase-1, matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-3 were measured through histologic and Western blot analyses. RESULTS: Ceffe significantly increased cell proliferation in cultured dermal fibroblasts. In the mouse skin, Ceffe significantly increased the thickness of the dermis, number of proliferating cells, density of the capillary, and expressions of Col-1 and Col-3. CONCLUSIONS: Ceffe increased the dermal thickness of nude mice, possibly by enhancing angiogenesis and extracellular matrix production, and can therefore be used for skin rejuvenation.

Fat Extract Improves Random Pattern Skin Flap Survival in a Rat Model.

BACKGROUND: Adipose tissue and its derivatives, including adipose-derived stem cells, stromal vascular fraction (SVF), and SVF-gel, have been utilized in the treatment of many ischemic disorders. However, the utilization of these products is limited in clinical applications by concerns related to the presence of cells in these derivatives. OBJECTIVES: This study aimed to isolate a cell-free fat extract (FE) from fat tissue and to evaluate its proangiogenic ability in vitro as well as its protective effects on skin flap survival in vivo. METHODS: FE was isolated from human fat via a mechanical approach. The concentrations of several growth factors in the FE were determined by enzyme-linked immunosorbent assay. The proangiogenic ability of FE was evaluated utilizing assays of the proliferation, migration, and tube formation in human umbilical vein endothelial cells in vitro. The protective effects of FE on the survival of random pattern skin flaps were investigated by subcutaneous injection into rats. RESULTS: Enzyme-linked immunosorbent assay results revealed that FE contained proangiogenic growth factors that promoted proliferation, migration, and tube formation in human umbilical vein endothelial cells in vitro. In addition, FE reduced skin flap necrosis and increased survival, as demonstrated by macroscopic measurements and blood flow analysis. Histological analysis revealed that FE treatment increased the capillary density. CONCLUSIONS: FE is a cell-free, easy-to-prepare, and growth-factor-enriched liquid derived from human adipose tissue that possesses proangiogenic activity and improves skin flap survival by accelerating blood vessel formation. FE may be potentially used for treating ischemic disorders.

Dual-Gated Transistor Platform for On-Site Detection of Lead Ions at Trace Levels.

On-site monitoring of heavy metals in drinking water has become crucial because of several high profile instances of contamination. Presently, reliable techniques for trace level heavy metal detection are mostly laboratory based, while the detection limits of contemporary field-based methods are barely meeting the exposure limits set by regulatory bodies such as the World Health Organization (WHO). Here, we show an on-site deployable, Pb2+ sensor on a dual-gated transistor platform whose lower detection limit is 2 orders of magnitude better than the traditional sensor and 1 order of magnitude lower than the exposure limit set by WHO. The enhanced sensitivity of our design is verified by numerically solving PNP (Planck-Nernst-Poisson) model. We demonstrate that the enhanced sensitivity is due to the suppression of ionic flux. The simplicity and the robustness of the design make it applicable for on-site screening, thereby facilitating rapid response to contamination events.

Expansion of CD26 positive fibroblast population promotes keloid progression.

BACKGROUND: Keloid is a skin fibrosis disease that characterised by invasive growth of fibroblasts and aberrant deposition of extracellular matrix. Studies indicated that keloid fibroblasts (KFs) is a class of 'activated' fibroblasts, which show accelerated proliferation and excessive extracellular matrix formation as compared with normal fibroblasts (NFs). However, the mechanism underlying keloid fibroblasts dysfunction is still unknown. OBJECTIVE: To verify CD26 expression difference between KFs and NFs, and investigate the function of CD26 positive fibroblasts in keloid progression. METHODS: KFs and NFs were isolated from Keloid tissues and normal skin tissues respectively. Flow cytometry was performed to isolate CD26+/CD26- fibroblasts from KFs and NFs. Proliferation of different fibroblasts were analyzed by CCK8 assay and Ki 67 straining. Profibrotic phenotype difference was detected by qRT-PCR, western blot, ELISA and immunofluorescence. Scratching experiment and transwell assay were used to assess invasion ability of CD26+/CD26- fibroblasts. Diprotin A was used as a CD26 inhibitor to further investigated the function of CD26 fibroblasts in keloid disease. RESULT: CD26 expression was increased in KFs, and the proportion of CD26+ fibroblasts was significantly increased in KFs. Cell viability analysis showed that CD26+ fibroblasts was more active in proliferation. Furthermore, the expression of profibrotic genes were increased in CD26+ fibroblasts, including TGF-ß1, IGF-1, IL6, collagen 1, collagen 3 and fibronectin. And meanwhile, CD26+ fibroblasts showed stronger invasion ability as compared to CD26- fibroblasts. Moreover, Diprotin A significantly suppressed proliferation and extracellular matrix secretion of CD26+ fibroblasts isolated from keloid tissues. CONCLUSION: Our findings suggest that CD26+ fibroblasts possess proliferation advantage in compare to CD26- fibroblasts, and the advantage caused expansion of CD26 positive fibroblast population promotes keloid progression.

Co-Transplantation of Nanofat Enhances Neovascularization and Fat Graft Survival in Nude Mice.

BACKGROUND: Autologous fat grafting is commonly used for soft-tissue augmentation and reconstruction. However, this technique is limited by a high rate of graft absorption. Thus, approaches to improve fat graft survival that promote neovascularization are of great interest. Nanofat has several beneficial features that may render it more suitable for clinical applications than other stem-cell based approaches. OBJECTIVES: We aimed to determine whether nanofat could enhance new vessel formation and improve the long-term retention of fat grafts. METHODS: Nanofat was processed via mechanical emulsification and filtration. Fat grafts were transplanted subcutaneously under the scalps of nude mice with different nanofat volumes or without nanofat. The grafted fat was dissected 12 weeks after transplantation. Graft weight and volume were measured, and histological evaluations, including capillary density measurement, were performed. RESULTS: The co-transplantation of fat with nanofat showed higher graft weight and volume retention, better histological structure, and higher capillary density compared to that in controls. However, there were no significant differences between the two nanofat volumes utilized. CONCLUSIONS: Nanofat can enhance neovascularization and improve fat graft survival, providing a potential clinically viable approach to fat graft supplementation in plastic and reconstructive surgery.

The treatment efficacy of bone tissue engineering strategy for repairing segmental bone defects under diabetic condition.

Background: Diabetes mellitus is a systematic disease which exert detrimental effect on bone tissue. The repair and reconstruction of bone defects in diabetic patients still remain a major clinical challenge. This study aims to investigate the potential of bone tissue engineering approach to improve bone regeneration under diabetic condition. Methods: In the present study, decalcified bone matrix (DBM) scaffolds were seeded with allogenic fetal bone marrow-derived mesenchymal stem cells (BMSCs) and cultured in osteogenic induction medium to fabricate BMSC/DBM constructs. Then the BMSC/DBM constructs were implanted in both subcutaneous pouches and large femoral bone defects in diabetic (BMSC/DBM in DM group) and non-diabetic rats (BMSC/DBM in non-DM group), cell-free DBM scaffolds were implanted in diabetic rats to serve as the control group (DBM in DM group). X-ray, micro-CT and histological analyses were carried out to evaluate the bone regenerative potential of BMSC/DBM constructs under diabetic condition. Results: In the rat subcutaneous implantation model, quantitative micro-CT analysis demonstrated that BMSC/DBM in DM group showed impaired bone regeneration activity compared with the BMSC/DBM in non-DM group (bone volume: 46 ± 4.4 mm3 vs 58.9 ± 7.15 mm3, *p < 0.05). In the rat femoral defect model, X-ray examination demonstrated that bone union was delayed in BMSC/DBM in DM group compared with BMSC/DBM in non-DM group. However, quantitative micro-CT analysis showed that after 6 months of implantation, there was no significant difference in bone volume and bone density between the BMSC/DBM in DM group (199 ± 63 mm3 and 593 ± 65 mg HA/ccm) and the BMSC/DBM in non-DM group (211 ± 39 mm3 and 608 ± 53 mg HA/ccm). Our data suggested that BMSC/DBM constructs could repair large bone defects in diabetic rats, but with delayed healing process compared with non-diabetic rats. Conclusion: Our study suggest that biomaterial sacffolds seeded with allogenic fetal BMSCs represent a promising strategy to induce and improve bone regeneration under diabetic condition.

Cell-free fat extract promotes axon regeneration and retinal ganglion cells survival in traumatic optic neuropathy.

Injuries to axons within the central nervous system (CNS) pose a substantial clinical challenge due to their limited regenerative capacity. This study investigates the therapeutic potential of Cell-free fat extract (CEFFE) in CNS injury. CEFFE was injected intravitreally after the optic nerve was crushed. Two weeks post-injury, quantification of regenerated axons and survival rates of retinal ganglion cells (RGCs) were performed. Subsequently, comprehensive gene ontology (GO) an-notation elucidated the cellular origins and functional attributes of CEFFE components. Molecular mechanisms underlying CEFFE's therapeutic effects were explored through Western blotting (WB). Additionally, levels of inflammatory factors within CEFFE were determined using enzyme-linked immunosorbent assay (ELISA), and histological staining of microglia was conducted to assess its impact on neuroinflammation. CEFFE demonstrated a significant capacity to promote axon re-generation and enhance RGCs survival. GO annotation revealed the involvement of 146 proteins within CEFFE in axonogenesis and neurogenesis. WB analysis unveiled the multifaceted pathways through which CEFFE exerts its therapeutic effects. Elevated levels of inflammatory factors were detected through ELISA, and CEFFE exhibited a modulatory effect on microglial activation in the retinal tissue following optic nerve crush (ONC). The present study highlights the therapeutic promise of CEFFE in the management of CNS injuries, exemplified by its ability to foster axon regeneration and improve RGCs survival.

The role and mechanism of engineered nanovesicles derived from hair follicle mesenchymal stem cells in the treatment of UVB-induced skin photoaging.

BACKGROUND: Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are effective in the treatment of skin photoaging; however, their low yield and functional decline with passage progression limit their clinical application. Cell-derived nanovesicles (CNVs) are potential alternatives that can address the limitations of EVs derived from MSCs and are conducive to clinical transformations. Hair follicle mesenchymal stem cells (HFMSCs), a type of MSCs, have demonstrated the function of repairing skin tissues; nevertheless, the efficacy of CNVs from HFMSCs (HFMSC-CNVs) in the treatment of skin photoaging remains unclear. Therefore, ultraviolet radiation B (UVB)-induced photoaging nude mice and human dermal fibroblasts (HDFs) were used as experimental models to investigate the therapeutic effects of HFMSC-CNVs in photoaging models. METHODS: HFMSC-CNVs were successfully prepared using the mechanical extrusion method. UVB-induced nude mice and HDFs were used as experimental models of photoaging. Multiple approaches, including hematoxylin-eosin and Masson staining, immunohistochemistry, immunofluorescence, detection of reactive oxygen species (ROS), flow cytometry, western blotting, and other experimental methods, were combined to investigate the possible effects and mechanisms of HFMSC-CNVs in the treatment of skin photoaging. RESULTS: In the nude mouse model of skin photoaging, treatment with HFMSC-CNVs reduced UVB-induced skin wrinkles (p < 0.05) and subcutaneous capillary dilation, alleviated epidermis thickening (p < 0.001), and dermal thinning (p < 0.001). Furthermore, HFMSC-CNVs upregulated proliferating cell nuclear antigen (PCNA) expression (p < 0.05) and decreased the levels of ROS, ß-galactosidase (ß-Gal), and CD86 (p < 0.01). In vitro experiments, treatment with HFMSC-CNVs enhanced the cellular activity of UVB-exposed HDFs (p < 0.05), and reduced ROS levels and the percentage of senescent cells (p < 0.001), and alleviated cell cycle arrest (p < 0.001). HFMSC-CNVs upregulated the expression of Collagen I (Col I), SMAD2/3, transforming growth factor beta (TGF-ß), catalase (CAT), glutathione peroxidase-1 (GPX-1), and superoxide dismutase-1 (SOD-1) (p < 0.05) and downregulated the expression of cycle suppressor protein (p53), cell cycle suppressor protein (p21), and matrix metalloproteinase 3 (MMP3) (p < 0.05). CONCLUSION: Conclusively, the anti-photoaging properties of HFMSC-CNVs were confirmed both in vivo and in vitro. HFMSC-CNVs exert anti-photoaging effects by alleviating cell cycle arrest, decreasing cellular senescence and macrophage infiltration, promoting cell proliferation and extracellular matrix (ECM) production, and reducing oxidative stress by increasing the activity of antioxidant enzymes.

In vitro study of the cytotoxicities of two mixed-ligand oxovanadium complexes on human hepatoma cells.

The cytotoxicities of two oxovanadium complexes, VOI [VO(satsc)(phen)] (satsc = salicylaldehyde thiosemicarbazone, phen = 1,10-phenanthroline) and VOII [VO(3,5-dibrsatsc)(phen)](3,5-dibrsatsc = 3,5-dibromosalicylaldehyde thiosemicarbazone), were studied by performing MTT assays on human hepatoma cell lines BEL-7402, HUH-7 and HepG2. The results showed that both the VOI and VOII complexes possess significant anti-proliferative effects. In addition, the anti-proliferative mechanism of the complexes was analyzed by cell cycle analysis and an apoptosis assay and by detecting the mitochondrial membrane potential (delta psi m). The experimental results showed that the complexes can cause a G0/G1 phase cell cycle arrest and can significantly decrease delta psi m, causing depolarization of the mitochondrial membrane. Notably, the two complexes induced apoptosis in BEL-7402 cells and displayed typical morphological apoptotic characteristics. The cytotoxicities of the VOII complex are significantly stronger than that of the VOI complex, suggesting that the cytotoxic effects of oxovanadium complexes may be associated with the electronic effects of the complexes.

Study of the upregulation of the activity of cytochrome P450 3A isoforms by Astragalus injection and Astragalus granules in rats and in cells.

Astragalus injection (AI) and Astragalus granules (AG) are the two representative clinical preparations from Astragali Radix. In order to investigate the regulation of metabolism, AI and AG were tested for their ability to affect the major enzyme cytochrome P450 3A isoforms in vivo and in vitro. In the study of CYP3A1 enzyme activity, male rats were pretreated with AI and AG. The "cocktail" approach-based LC-MS/MS results showed that AI pretreatment at 0.16, 0.8 and 4 g kg(-1) day(-1) significantly increased the rat liver microsome CYP3A1 activity by 1.62-, 1.68- and 2.00-fold, and AG pretreatment at 32, 160 and 800 mg kg(-1) day(-1) significantly increased the rat CYP3A1 activity by 1.86-, 2.16- and 1.76-fold. The effects of AI and AG on liver microsome CYP3A1 mRNA expression in rats were analyzed using real-time PCR technique. The results showed that AI and AG pretreatments significantly increased the CYP3A1 mRNA expression. The induction of CYP3A4 enzyme activity by AI and AG in vitro was measured using a CYP3A4 luciferase reporter gene assay in transiently transfected human intestinal LS174T cells. Compared to the control group, AI at 62.5-1,000 mg/ml could significantly induce CYP3A4 reporter gene luciferase activity of 1.36- to 1.88-fold for 48-h incubated PXR-transfected LS174T cells, and AG at 62.5-1,000 µg/ml significantly transactivated CYP3A4 reporter gene luciferase activity of 1.36- to 2.05-fold. However, the CYP3A4 reporter gene construct was not significantly transactivated by the AI and AG in CAR-transfected LS174T cells. These CYP3A isoforms upregulation results can help us to use AI and AG rationally in the clinic.

Dynamic optimal allocation of medical resources: a case study of face masks during the first COVID-19 epidemic wave in the United States.

In this paper, we propose a two-group SIR epidemic model to simulate the outcome of the stay-at-home policy and the imposed face mask policy during the first COVID-19 epidemic wave in the United States. Then, we use a dynamic optimal control approach (with the objective of minimizing total deaths) to find the optimal dynamical distribution of face masks between healthcare workers and the general public. It is not surprising that all face masks should be solely reserved for healthcare workers if the supply is short. However, when the supply is indeed sufficient, our numerical study indicates that the general public should share a large portion of face masks at the beginning of the epidemic wave to dramatically reduce the death toll. This interesting result partially contradicts the guideline advised by the US Surgeon General and the Centers for Disease Control and Prevention (CDC) in March 2020. The optimality of this sounding CDC guideline highly depends on the supply level of face masks, which changes frequently; hence, it should be adjusted according to the supply of face masks.